Differential modulation of transendothelial electrical resistance by TRPV4 agonists is mediated by apoptosis and/or necrosis

N Pairet; S Mang; T Kiechle; N Laufhäger; P Dietl; D J Lamb

doi:10.1016/j.bbrep.2019.100672

Differential modulation of transendothelial electrical resistance by TRPV4 agonists is mediated by apoptosis and/or necrosis

Biochem Biophys Rep. 2019 Sep 19:20:100672. doi: 10.1016/j.bbrep.2019.100672. eCollection 2019 Dec.

Authors

N Pairet^{1

2}, S Mang^{3

4}, T Kiechle³, N Laufhäger³, P Dietl¹, D J Lamb³

Affiliations

¹ Institute of General Physiology, University of Ulm, Ulm, Germany.
² Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, D-88397, Biberach an der Riß, Germany.
³ Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, D-88397, Biberach an der Riß, Germany.
⁴ Institute of Immunology, Hannover Medical School, D-30625, Hannover, Germany.

Abstract

Transient receptor potential vanilloid 4 (TRPV4) has been implicated in many disease conditions also in the lung. Its activation leads to an increase endothelial permeability in an intracellular calcium-influx dependent manner. We investigated its function in vitro on primary human endothelial cells using two TRPV4 agonists, GSK1016790A and 4α-Phorbol 12,13-didecanoate (4α-PDD) and a selective TRPV4 blocker GSK2193874. Both TRPV4 agonists leaded to a reduction in transendothelial electrical resistance (TER) which was mediated however by differential cytotoxic effects. 4α-PDD induced apoptosis that could not be blocked by TRPV4 inhibition in HUVECs, whereas GSK1016790A selectively activated TRPV4 and reduced TER as a consequence of cellular necrosis. TRPV4 mediated cytotoxicity is poorly described and may provide significant context to the role of TRPV4 in barrier-function.